4-186079102-C-G

Variant names:

• chr4-186079102-C-G
• rs5743312
• NM_003265.3:c.633+71C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003265.3(TLR3):​c.633+71C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000858 in 1,165,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: TLR3 NM_003265.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.872
• Publications: 0 publications found

Genes affected

TLR3 (HGNC:11849): (toll like receptor 3) The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This receptor is most abundantly expressed in placenta and pancreas, and is restricted to the dendritic subpopulation of the leukocytes. It recognizes dsRNA associated with viral infection, and induces the activation of NF-kappaB and the production of type I interferons. It thus plays a role in host defense against multiple viruses. [provided by RefSeq, Jul 2021]

TLR3 Gene-Disease associations (from GenCC):

• immunodeficiency 83, susceptibility to viral infections

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR3	NM_003265.3	c.633+71C>G		intron_variant	Intron 3 of 4	ENST00000296795.8	NP_003256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR3	ENST00000296795.8	c.633+71C>G		intron_variant	Intron 3 of 4	1	NM_003265.3	ENSP00000296795.3
TLR3	ENST00000513189.1	n.633+71C>G		intron_variant	Intron 3 of 4	1		ENSP00000423386.1
TLR3	ENST00000698351.1	c.633+71C>G		intron_variant	Intron 3 of 4			ENSP00000513674.1
TLR3	ENST00000698352.1	n.*185+71C>G		intron_variant	Intron 3 of 4			ENSP00000513675.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.58e-7 AC: 1 AN: 1165934 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 588130

African (AFR) AF: 0.00 AC: 0 AN: 26946

American (AMR) AF: 0.00 AC: 0 AN: 36690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23596

East Asian (EAS) AF: 0.00 AC: 0 AN: 35650

South Asian (SAS) AF: 0.00 AC: 0 AN: 74534

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50240

Middle Eastern (MID) AF: 0.000277 AC: 1 AN: 3612

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 864498

Other (OTH) AF: 0.00 AC: 0 AN: 50168

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.060
DANN	Benign	0.44
PhyloP100		-0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs5743312; hg19: chr4-187000256;